Selective N-alkylation of indoles with primary alcohols using a pt/HBEA catalyst?

Article abstract of DOI:10.1039/c4gc01419g

Pt-loaded HBEA (H⁺-exchanged BEA zeolite) is found to be an effective and reusable heterogeneous catalyst for regioselective N-alkylation of indoles with primary aliphatic and benzylic alcohols under additive-free conditions driven by the borrowing-hydrogen methodology. Structural and mechanistic studies suggest a cooperative mechanism of the Pt⁰ site on Pt metal clusters and the Br?nsted acid site of the zeolite, in which the Pt⁰ site is responsible for dehydrogenation/hydrogenation steps and the Br?nsted acid site is responsible for the regioselective condensation of indoles with aldehydes to the enamine intermediate.

Full text of DOI:10.1039/c4gc01419g

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Selective N-alkylation of indoles with primary alcohols by Pt/HBEA catalyst
S. M. A. Hakim Siddiki,a Kenichi Kon,b Ken-ichi Shimizu*a,b
a
Elements Strategy Initiative for Catalysts and Batteries, Kyoto University, Katsura, Kyoto
615-8520, Japan
b Catalysis Research Center, Hokkaido University, N-21, W-10, Sapporo 001-0021, Japan
*Corresponding author
Ken-ichi Shimizu
Catalysis Research Center, Hokkaido University, N-21, W-10, Sapporo 001-0021, Japan
E-mail: kshimizu@cat.hokudai.ac.jp, Fax: +81-11-706-9163
Abstract: Pt-loaded HBEA (H+-exchanged BEA zeolite) is found to be effective and reusable
heterogeneous catalyst for regioselective N-alkylation of indoles with primary aliphatic and
benzylic alcohols under additive-free conditions driven by borrowing-hydrogen methodology.
Structural and mechanistic studies suggest a cooperative mechanism of Pt0 site on Pt metal clusters
and Brønsted acid site of the zeolite, in which Pt0 site is responsible for
dehydrogenation/hydrogenation steps and the Brønsted acid site is responsible for the regioselective
condensation of indoles with aldehyde to enamine intermediate.
Indoles are relevant structures in heterocyclic natural products, pharmaceutical ingredients,
functional materials and agro-chemicals. Hence, attentions have been focused on the improved
methodologies for synthesis and functionalization of indoles.1-4 Among the indole derivatives,
N-substituted indoles are of particular importance for the construction of various biologically active
molecules.5-7 Generally, C3-position of indole has greater nucleophilicity than N-position, which
makes N-selective alkylation of indoles difficult. The classical approach for the N-alkylation of
indoles is the base-catalyzed reaction of indole with an alkyl halide,8,9 which suffers from
quantitative formation of salt wastes. Use of alcohol as a more benign and abundant alkyl source
can overcome this drawback. Earlier example is the N-alkylation of indoles with alcohols by excess
amount of Raney nickel.10 In contrast to these classical methods, transition-metal catalyzed
hydrogen transfer (borrowing hydrogen) methodology11-15 can provide more atom-efficient
alkylation method using alcohols. As for the C3-alkylation of indoles by alcohols, homogeneous Ir
catalysts16,17 first reported by Grigg16 and heterogeneous Pt/Al2O3 catalyst recently reported by our
group18 were shown to be effective. In contrast, N-alkylation of indoles by alcohols has been rarely
exploited. Only one successful example is a Ru-based Shvo catalyst with a Brønsted acidic
co-catalyst reported by Beller, Williams and co-workers.19 However, this homogeneous method still
has some drawbacks such as low turnover number (TON), difficulty in catalyst/product separation,
and necessities of acidic additive (0.025 mol% PTSA) and excess molar amount (2 equiv.) of
alkylating agent. Shi et al. showed N-alkylation of indole with excess amount of benzyl alcohol at
170 °C using an iron oxide immobilized Pd catalyst,20 but the substrate scope was limited to only
one example. As a part of our continuing interest in the heterogeneous catalysis for
hydrogen-transfer reactions by Pt nanocluster catalysts,18,21-23 we report herein a heterogeneous
catalytic system for the selective N-alkylation of indoles with alcohols by Pt nanocluster-loaded
HBEA zeolite24 (Pt/HBEA). To our knowledge, this is the first general heterogeneous catalysis of
1

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N-alkylation of indole by various aliphatic and benzyl alcohols without any promoter. Additionally,
a combination of this work and our previous work18 demonstrates the first example of
support-controlled complete selectivity switch in regioselective alkylation of indole with primary
alcohols by heterogeneous Pt cluster catalysts (Scheme 1).
To optimize the catalyst composition, the reaction of equimolar amounts of 1-octanol and indole
was tested under N2 at 130 °C for 22 h with various catalysts pre-reduced in H2 at 300 °C (Table 1).
Using various transition metals (5 wt% Pt, Ir, Re, Pd, Rh, Ru, Ag, Co, Ni or Cu) supported on HY
zeolite (entries 1-10), we carried out a preliminary catalyst screening test. Among the catalysts
tested, Pt/HY showed the highest yield of the N-alkylated indole. Then, we studied the effect of
support materials on 5 wt% Pt loaded catalysts (entries 1, 11-20). As reported in our previous study
on C-3 alkylation of indole,18 use of an acid-base bifunctional support, Al2O3, resulted in selective
formation of the C-3 adduct with 56% yield (entry 14). In contrast, Pt catalysts supported on acidic
supports such as HY zeolite (entry 1), TiO2 (entry 15), silica-alumina (entry 16), and HBEA (entry
20) selectively catalyzed the N-alkylation of indole, and the yields of N-adduct was 19-87%.
Pt/HBEA (entry 20) showed the highest yield of N-alkylated product (87%) with no formation of
the C3-adduct. Pt catalysts on HMFI zeolite with narrow pore size (< 0.56 nm), basic (MgO, CeO2),
and neutral supports (SiO2, C) were nearly inactive, and the yield of C3- and N-adducts were below
1%. HBEA itself (entry 22) is inactive, indicating that Brønsted acid of HBEA itself does not
catalyze the N-alkylation of indole. To verify the necessity of Brønsted acid site of Pt/HBEA we
studied poisoning effect of a basic additive (pyridine) which is known to neutralize the Brønsted
acid sites of HBEA. The presence of 0.05 mmol of pyridine in the reaction mixture resulted in
complete deactivation of Pt/HBEA (entry 21). From these results, we can conclude that Brønsted
acid site of Pt/HBEA is an important co-catalyst.
To study the structure of Pt species, we carried out spectroscopic characterizations of Pt/HBEA.
The X-ray absorption near edge structure (XANES) of Pt/HBEA was almost identical to that of Pt
foil (Figure S1 in the supporting information), indicating the metallic state of the Pt species in
Pt/HBEA. The analysis of Pt L3-edge extended X-ray absorption fine structure (EXAFS) showed
Pt–Pt coordination number of 10.2 at the distance of 2.74 Å (Figure S1 and Table S1). This result
also shows the metallic state of the Pt species in Pt/HBEA. Figure S2 shows size distribution of Pt
particle on the outer surface of Pt/HBEA observed by TEM. The mean diameter from TEM analysis
(3.3  0.7 nm) was larger than that from the CO adsorption experiment (1.8 nm). Considering that
small Pt clusters inside zeolite can not be observed by TEM, the results suggest that small Pt
clusters are present inside the micropore of HBEA zeolite. From these results, it can be concluded
that dominant Pt species in Pt/HBEA is the metallic Pt nanocluster with average size of 1.8 nm.
Next we discuss the structure of the active Pt species. Platinum oxides-loaded HBEA
(PtOx/HBEA, entry 23) showed no activity, indicating that oxides of Pt are inactive. Pt/HBEA-air
(entry 24), prepared by exposing the reduced Pt/HBEA to the ambient conditions for 0.5 h, showed
lower yield (46%) than as-reduced Pt/HBEA (87%). Figure S3 compares IR spectra of CO adsorbed
on Pt/HBEA and Pt/HBEA-air. The spectrum for Pt/HBEA shows a band at 2080 cm-1 due to the
linear coordination of CO on a Pt atom25 and a weak band at 1835 cm-1 due to bridged CO on two Pt
atoms. The spectrum for Pt/HBEA-air showed a band at 2080 cm-1 with lower intensity than
Pt/HBEA. This indicates that the surface metallic Pt0 sites of Pt/HBEA are partially oxidized by air
even at room temperature. Combined with the catalytic result, it is shown that the surface metallic
Pt0 sites are the active species. Taking into account that Brønsted acid site of HBEA is also required
2

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for the catalytic system, we can conclude that co-presence of Pt0 sites and Brønsted acid sites of
HBEA is indispensable to the catalytic system.
For the reaction of indole with 1-octanol, Pt/HBEA was removed from the reaction mixture at 3
h (3 yield = 20%). Then, further heating of the filtrate at 130 °C for 21 h did not increase the yield.
ICP-AES analysis of the filtrate confirmed that the content of Pt in the solution was below the
detection limit (10 ppb). Figure 1 shows the result of catalyst reuse. After the reaction, the catalyst
was separated by centrifugation, followed by washing with acetone, and by drying at 90 °C for 3 h,
and by H2-reduction at 300 °C for 0.5 h. The catalyst was reused at least three times without a
marked loss of its activity. These results indicate that Pt/HBEA acts as a reusable heterogeneous
catalyst.
Table 2 shows substrate scope for the reaction of equimolar amounts of indoles and alcohols by
1 mol% of Pt/HBEA. Various aliphatic alcohols including linear and branched aliphatic alcohols
(entries 1-10) were completely converted to yield the N-alkylated indoles with good isolated yields
(73-87%). Benzylalcohol (entry 11) was converted to the N-alkylated indole in 77% yield.26 Benzyl
alcohols with electron-withdrawing and electron-donating substituents (entries 13-15) were also
converted to N-alkylated indoles in 55-66% yields.27 Note that the previous method19 was only
applicable to the reaction of an activated (methoxide substituted) indole with benzyl alcohols.
N-alkylation of 3-methyl indole and 5-methyl indole with 1-octanol (entries 16 and 17) resulted in
excellent yields (85% and 93%). N-Alkylation of indole with a secondary alcohol (2-octanol)
resulted in 5% yield. For all the reaction in Table 2, C3-alkylated indoles were not observed in
GCMS analyses. This indicates that the present method is completely regioselective. Using small
amount of the catalyst (0.1 mol%), N-alkylation of indole with 1-octanol (entry 2), 1-hexanol (entry
4) and benzylalcohol (entry 12) gave 80, 85 and 70% yields, corresponding to TON of 800, 850,
and 700 respectively. TON for the reaction of indole with 1-hexanol is 4 times higher than that of a
Ru complex (TON of 213 per Ru atom),19 and TON for reaction of indole with benzyl alcohol is 3
times higher than that of Pd/Fe2O3 (TON of 213).20
Similar to the proposed mechanism for the C3-alkylation of indole with alcohols by Pt/Al2O3
(Scheme 2, lower part),18 the present reaction may proceed through the hydrogen-borrowing
pathway, which starts with dehydrogenation of primary alcohol. In the present system with
Pt/HBEA, nucleophilic attack of N atom of indole to aldehyde can result in the formation of
enamine intermediate (iminium ion intermediate for benzylic alcohol),19 which is re-hydrogenated
by Pt-H species (Scheme 2). The presumed pathway is supported by the following results. The
reaction of n-octanal and indole (eq. 1) with Pt/HBEA under N2 resulted in the formation of the
enamine 3a in 61% yield because of the absence of PtH species. In the presence of hydrogen-donor
(2-propanol), the same reaction (eq. 2) resulted in 60% yield of the N-alkylated indole, which can
be formed by transfer hydrogenation28,29 of the enamine intermediate 3a by 2-propanol.
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To discuss the origin of the support-depended switch of the regioselectivity between Pt/HBEA
(to N-adduct) and Pt/Al2O3 (to C3-adduct), we conducted the test reaction of n-octanal with indole
with Pt-unloaded support materials (HBEA or Al2O3). The result showed that the regioselectivity
completely depended on the support; HBEA gave only the enamine 3a (eq. 3), whereas Al2O3 gave
only the C3-adduct 3b (eq. 4). Interaction between Brønsted acid site of HBEA and C=C bond of
indole may reduce the nucleophilicity of C3 carbon, and instead nucleophilic attack of N atom of
indole to aldehyde results in the formation of the enamine intermediate.
To get further insight into the mechanism of the present catalytic reaction, the kinetic isotopic
effect (KIE) was investigated by the reaction of indole and α-deutero benzylalcohol (benzyl-α,α-d2
alcohol), and a moderate kH / kD value of 2.3 was obtained (Figure S4). The relative rates of
N-alkylation from indole and para-substituted benzylalcohols (X = OMe, Me, H, F, Cl, and CF3)
were also examined. A reasonable linearity between the log(kX / kH) values and the Hammett
parameters (σ) was obtained (Figure S5), suggesting that the transition state in the rate-determining
step of the alkylation reaction involves a positive charge at α-carbon atom adjacent to the phenyl
ring, which is stabilized by electrondonating substituents. The results of KIE and Hammett plot
indicate that dissociation α-C-H bond of benzylalcohol is a relatively slow step.
In summary, we developed the first additive-free, heterogeneous and reusable catalytic method
for regioselective N-alkylation of indoles with various primary alcohols using Pt/HBEA catalyst
driven by the borrowing-hydrogen mechanism. Compared with the previous homogeneous catalytic
system, our method has the following advantages: (1) easy catalyst/product separation, (2) catalyst
reusability, (3) higher TON, (4) additive-free conditions, and (5) no need of excess amount of
alcohol. Structural and mechanistic studies suggest that this system is driven by cooperation of Pt0
sites on the surface of Pt cluster and Brønsted acid site in the zeolite in which Pt0 sites are
responsible for dehydrogenation/hydrogenation steps and the Brønsted acid site is responsible for
the regioselective condensation of indoles with aldehyde to enamine intermediate.
Acknowledgment
This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas "Nano
Informatics" (25106010) from JSPS and a MEXT program "Elements Strategy Initiative to Form
Core Research Center".
Notes and references
1 R. J. Sundberg, Indoles; Academic Press: San Diego, 1996.
2 K. Krger, A. Tillack and M. Beller, Adv. Synth. Catal., 2008, 350, 2153.
3 G. R.Humphrey and J. T. Kuethe, Chem. Rev., 2006, 106, 2875.
4 S. Cacchi, G. Fabrizi, Chem. Rev., 2005, 105, 2873.
4

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5 M. Negwer, H.-G. Scharnow, Organic-Chemical Drugs and Their Synonyms, Vol. 3, 9th ed.,
Wiley-VCH, Weinheim, 2007, p. 1915.
6 M. Negwer and H.-G. Scharnow, Organic-Chemical Drugs and Their Synonyms, Vol. 4, 9th ed.,
Wiley-VCH, Weinheim, 2007, p. 2631.
7 M.Negwer and H.-G.Scharnow, Organic-Chemical Drugs and Their Synonyms, Vol. 4, 9th ed.,
Wiley-VCH, Weinheim, 2007, p. 2632.
8 a) G. Vavilina, A. Zicmanis, S. Drozdova, P. Mekss and M. Klavins, Chem. Heterocycl. Compd.,
2008, 44, 530; b) A. V. Karchava, F. S. Melkonyan and M. A. Yurovskaya, Chem. Heterocycl.,
Compd. 2012, 48, 391.
9 Y. R. Jorapur, J. M. Jeongb and D. Y.Chi, Tetrahedron Lett., 2006, 47, 2435.
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13 R. Yamaguchi, K. Fujita and M.Zhu, Heterocycles, 2010, 81, 1093.
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Mol. Divers., 2010, 14, 411.
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17 A. E. Putra, K. Takigawa, H. Tanaka, Y. Ito, Y. Oe and T. Ohta, Eur. J. Org. Chem., 2013, 6344.
18 S. S. M. A. Hakim, K. Kon and K. Shimizu, Chem. Eur. J., 2013, 19, 14416.
19 S. Bahn, S. Imm, K. Mevius, L. Neubert, A. Tillack, J. M. J. Williams and M. Beller, Chem. Eur.
J., 2010, 16, 3590.
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21 K. Kon, S. S. M. A. Hakim and K. Shimizu, J. Catal., 2013, 304, 63.
22 C. Chaudhari, S. S. M. A. Hakim and K. Shimizu, Tetrahedron Lett., 2013, 54, 6490.
23 S. S. M. A. Hakim, K. Kon, A. S. Touchy and K. Shimizu, Catal. Sci. Technol., 2014, 4, 1716.
24 Catalysis Society of Japan supplies the HBEA sample (JRC-Z-HB25), which is originally
supplied as B-25 from Clariant Catalysts.
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26 Michael addition adduct (3,3ʹ-bisindolyl phenylmethane) was observed as a byproduct (8%
yield).
27 GCMS analysis showed that relatively low yields for benzyl alcohols were due to the formation
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Yus, ChemCatChem, 2009, 1, 75.
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Table 1. Reaction of 1 with 2 by various catalysts.a
1 mol%
catalyst
C8H17
OH
o-xylene (1 g)
130 oC, 22 h
N
H
N
N
H
C8H17
1 mmol
1 mmol
1
2
3
4
Conv.
(%)
3 yield
(%)
4 yield
(%)
Entry Catalysts
1
2
Pt/HY
Ir/HY
51
8
40
0
0
0
0
0
0
0
0
0
0
0
0
0
0
56
2
1
1
0
0
0
0
0
0
0
3
Re/HY
Pd/HY
Rh/HY
Ru/HY
Ag/HY
Co/HY
Ni/HY
Cu/HY
Pt/MgO
Pt/CeO2
Pt/ZrO2
Pt/Al2O3
Pt/TiO2
Pt/SiAl
Pt/SiO2
Pt/C
6
0
4
8
0
5
4
0
6
8
0
7
8
0
8
9
0
9
6
0
10
11
12
13
14
15
16
17
18
19
20
4
0
10
15
13
66
68
30
8
0
0
5
3
54
19
0
7
0
Pt/HMFI
Pt/HBEA
5
0
100
5
87
0
21b Pt/HBEA
22c
23
24
HBEA
6
0
12
65
0
PtOx/HBEA
Pt/HBEA-air
46
a Conversion of 1 and yields were determined by GC.
b In the presence of pyridine (0.05 mmol).
c 39 mg of HBEA.
6

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Table 2. N-Alkylation of indoles with different alcohols by Pt/HBEA.a
Isolated
Entry
Alcohols
Products
yield (%)
82 (87)b
80b
1
2c
3
N
OH
C7H15
OH
87
N
C5H11
4c
85b
OH
N
5
6
85
87
C9H19
N
OH
C11H23
7d
8d
77
82
OH
N
N
OH
OH
N
9
73
81
10
N
OH
N
OH
11
12c
13
77
70b
60
OH
OH
N
F
N
14
15
55
66
F
N
OH
OH
16
17
85
93
N
C7H15
N
OH
C7H15
a Conditions: 0.01 mmol Pt (1 mol%), 1 mmol indole, 1 mmol alcohol, 1g o-xylene, 130 °C, 22 h.
b GC yield. c 0.001 mmol Pt (0.1 mol%), 90 h. d 1.5 g o-xylene.
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this work
our works
X
Pt/HBEA
o-xylene, 130 °C
N
X
R
R
OH
N
H
ref. 18
R
Pt/Al2O3
X
o-xylene, reflux
N
H
Scheme 1. Support-controlled complete selectivity switch in alkylation of indole with primary
alcohols by heterogeneous Pt catalysts.
this work
PtH2
Pt
H+ of HBEA
N
N
Pt
PtH2
R
R
OH
R
O
R
PtH2
R
R
Pt
Al2O3
N
N
N
H
H
ref. 18
Scheme 2. Presumable pathways of N-alkylation (by Pt/HBEA) and C3-alkylation (by Pt/Al2O3)18
of indole with primary alcohols.
Figure 1. Catalyst reuse for N-alkylation of indole by 1-octanol by Pt/HBEA. Conditions are shown
in Table 2.
8